Sjögren's syndrome affects up to 4 million people in the United States, 90% of whom are women. Patients with this autoimmune disease, which targets and destroys exocrine glands, such as the tear (lacrimal) and salivary glands, often experience the classic symptoms of severe dry mouth and/or eyes. Patients with Sjögren's syndrome are at an increased risk of infection and/or damage to these organs (e.g. corneal scarring, dental decay, gingivitis). They may also experience complications related to the destruction of other moisture-producing glands, or have systemic complications, such as disabling fatigue, joint pain and stiffness, or dysfunction of the heart, blood vessels, lung, liver, nerves, or kidney. Currently, there is no cure for Sjögren's syndrome. Treatment is focused on symptom relief and on prevention and treatment of complications.
As with many other autoimmune diseases, the underlying cause of Sjögren's syndrome is driven in part by the presence of abnormal T cells that are reactive to self proteins. Although diverse animal models are studied in Sjögren's syndrome, the non-obese diabetic (NOD) murine model of spontaneous diabetes and Sjögren's syndrome is frequently studied to understand early T cell education pathways that contribute to disease. NOD mice clinically show symptoms similar to human Sjögren's syndrome, such as reduced saliva production, presence of lymphocytic infiltrates in the salivary glands, and genetic linkage of the disease to the gene cluster known in the human as the MHC (HLA) class II region. The MHC region contains not only the HLA class II genes themselves, but a diversity of MHC class I processing genes, such as Tap (Ham) and the LMP genes (e.g., LMP-2, LMP-7). The LMP genes and proteins are part of the cytoplasmic proteasome complex (FIG. 1) that acts as a protein processing station by taking long peptides and breaking them into fragments that allow MHC class I assembly into the class I exterior facing groove. Originally, the MHC class I processing gene was thought to have an exclusive role in peptide presentation for host defense during intracellular viral infections. Later it was discovered that antigen presenting cells have defects in MHC class I assembly in the NOD mice and in humans with autoimmunity. Further studies of the MHC class I pathway in the NOD mice revealed that the interrupted antigen processing was due to the lack of production of the LMP-2 proteasome protein in the immune system in young mice progressing towards disease.
Diagnosis of Sjögren's syndrome is based on a combination of blood tests, tissue studies (e.g., salivary gland biopsy), and physical exams to detect symptoms. In general, a positive diagnosis involves having at least 4 out of 6 symptoms from a list that includes dry mouth, dry eye, ocular involvement, evidence of lymphocytic infiltrates into the minor salivary glands (through lip biopsy), impaired salivary gland function, and serum autoantibodies against Ro[SSA] and/or La[SSB] antigens. This diagnostic system is imprecise, with a significant false negative rate owing to lip biopsies that miss small, early sites of inflammation and low-titer autoantibody tests. In addition, lip biopsy is undesirable for many patients, since it may cause disfigurement or additional damage to an organ that is already dysfunctional.
Thus, there is a need for effective diagnostic tests for Sjögren's syndrome that improve detection of this difficult-to-diagnose disease.